4-(1H-indol-1-yl)-1-piperidinyl derivatives

ABSTRACT

The present invention concerns the compounds of formula ##STR1## the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein the dashed line designates an optional bond; R 1  and R 2  are each independently hydrogen, halogen, C 1-6  alkyl or C 1-6  alkyloxy; R 3  and R 4  are each independently hydrogen, C 1-6  alkyl, phenyl or phenyl substituted with one, two or three substituents selected from halo, hydroxy, nitro, cyano, trifluoromethyl, C 1-6  alkyl, C 1-6  alkyloxy, C 1-6  alkylthio, mercapto, amino, mono- and di(C 1-6  alkyl)-amino, carboxyl, C 1-6  alkyloxycarbonyl and C 1-6  alkylcarbonyl; Alk is C 1-4  alkanediyl; D is a pyrimidinone, piperidone or a benzimidozolidinone; having antipsychotic activity; their preparation, compositions containing them and their use as a medicine.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a 371, the national stage of application No. PCT/EP96/00363, filed on Jan. 23, 1996, which application claims priority fromEP 95.200.229.3, filed on Jan. 31, 1995.

The present invention concerns 4-(1H-indol-1-yl)-1-piperidinylderivatives having therapeutic potential in psychotic disorders. Itfurther relates to their preparation, compositions comprising them andtheir use as a medicine.

In EP-A-0,037,265, published on Oct. 7, 1981, EP-A-0,070,053, publishedon Jan. 19, 1983, and in EP-A-0,378,255, published on Jul. 18, 1990,there are described a number of 5-4-(1H-indol-3-yl)-1-piperidinyl!alkyl!-4(3H)-pyrimidinone derivativeshaving antipsychotic, antihistaminic and antiserotonergic activity.Structurally, the compounds of the present invention differ therefrom inthat the 4 position of their piperidine moiety is invariably substitutedby a 1H-indol-1-yl derivative.

EP-A-0,470,039, published on Feb. 5, 1992, discloses4-(3-aryl-1H-indol-1-yl)-1-piperidinyl derivatives as selectiveantagonists of the serotonin 5-HT₂ receptor without substantial dopamineD-2 antagonistic activity both in vivo and in vitro. Said selectiveantagonistic property is measured as the ratio between the dopamine D-2receptor and the serotonin 5-HT₂ receptor antagonistic activities.Unexpectedly, the compounds of the present invention differ therefrom inthat they exhibit central dopamine and central serotonin antagonisticactivity in vivo in similar dose-ranges, i.e. the ratio between centraldoparninergic and central serotonergic activity is about unity.

The compounds of the present invention show antipsychotic activity withan unexpected increased cardiovascular safety, i.e. they show animproved dissociation between the peripheral α-adrenergic antagonisticactivity and the central dopamine and serotonin antagonistic activity.

The present invention concerns the compounds of formula ##STR2## thepharmaceutically acceptable addition salts and the stereochemicallyisomeric forms thereof, wherein:

the dashed line designates an optional bond;

R¹ and R² are each independently hydrogen, halogen, C₁₋₆ alkyl or C₁₋₆alkyloxy;

R³ and R⁴ are each independently hydrogen, C₁₋₆ alkyl, phenyl or phenylsubstituted with one, two or three substituents selected from halo,hydroxy, nitro, cyano, trifluoromethyl, C₁₋₆ alkyl, C₁₋₆ alkyloxy, C₁₋₆alkylthio, mercapto, amino, mono- and di(C₁₋₆ alkyl)amino, carboxyl,C₁₋₆ alkyloxycarbonyl and C₁₋₆ alkylcarbonyl;

Alk is Cl 4alkanediyl;

D is a radical of formula ##STR3## wherein R⁵ is hydrogen or C₁₋₆ alkyl;

R⁶ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkyloxy, C₁₋₆ alkylthio, amino ormono- or di(C₁₋₆ alkyl)amino; and

R⁷ is hydrogen or C₁₋₆ alkyl; or

R⁶ and R⁷ taken together may form a bivalent radical --R⁶ --R⁷ --, inparticular, --R⁶ --R⁷ -- may be

    ______________________________________    --CH.sub.2 --CH.sub.2 --CH.sub.2 --                            (a-1);    --CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 --                            (a-2);    --CH═CH--CH.sub.2 --                            (a-3);    --CH.sub.2 --CH═CH--                            (a-4) or    --CH═CH--CH═CH--                            (a-5);    ______________________________________

wherein one or two hydrogen atoms of said radicals (a-1) to (a-5) eachindependently may be replaced by C₁₋₆ alkyl, hydroxy, C₁₋₆ alkyloxy orC₁₋₁₀ alkylcarbonyloxy; or --R⁶ --R⁷ -- may also be

    ______________________________________    --S--CH.sub.2 --CH.sub.2 --                            (a-6);    --S--CH.sub.2 --CH.sub.2 --CH.sub.2 --                            (a-7);    --S--CH═CH--        (a-8);    --NH--CH.sub.2 --CH.sub.2 --                            (a-9);    --NH--CH.sub.2 --CH.sub.2 --CH.sub.2 --                            (a-10);    --NH--CH═CH--       (a-11);    --NH--CH═N--        (a-12);    --S--CH═N--         (a-13) or    --CH═CH--O--        (a-14);    ______________________________________

wherein one or where possible two or three hydrogen atoms in saidradicals (a-6) to (a-14) each independently may be replaced by C₁₋₆alkyl; or D is a radical of formula ##STR4## wherein R⁸ is hydrogen orC₁₋₆ alkyl.

As used in the foregoing definitions the term halogen is generic tofluoro, chloro, bromo and iodo. The term C₁₋₄ alkyl defines straight andbranched saturated hydrocarbons, having from 1 to 4 carbon atoms suchas, for example, methyl, ethyl, propyl, butyl, 1-methylethyl,1,1-dimethylethyl, 2-methylpropyl. The term C₁₋₆ alkyl is meant toinclude C₁₋₄ alkyl radicals and the higher homologues thereof having 5or 6 carbon atoms such as, for example, pentyl, hexyl and the like. Theterm C₁₋₁₀ alkyl is meant to include C₁₋₆ alkyl radicals and the higherhomologues thereof having 7 to 10 carbon atoms such as, for example,heptyl, octyl, nonyl, decyl and the like. The term C₂₋₄ alkanediyldefines bivalent straight or branch chained alkanediyl radicals havingfrom 2 to 4 carbon atoms such as, for example, 1,2-ethanediyl,1,3-propanediyl, 1,4-butanediyl and the like. The term C₁₋₄ alkanediylis meant to include C₂₋₄ alkanediyl radicals and the lower homologue,i.e. 1,1-methanediyl.

The addition salts as mentioned herein are meant to comprise thetherapeutically active addition salt forms which the compounds offormula (I) are able to form with appropriate acids, such as, forexample, inorganic acids such as hydrohalic acids, e.g. hydrochloric orhydrobromic acid; sulfuric; nitric; phosphoric and the like acids; ororganic acids such as, for example, acetic, propanoic, hydroxyacetic,lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic,tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic,p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and thelike acids.

The pharmaceutically acceptable addition salts as mentioned hereinaboveare also meant to comprise the therapeutically active non-toxic base, inparticular, a metal or amine addition salt forms which the compounds offormula (I) are able to form. Said salts can conveniently be obtained bytreating the compounds of formula (I) containing acidic hydrogen atomswith appropriate organic and inorganic bases such as, for example, theammonium salts, the alkali and earth alkaline metal salts, e.g. thelithium, sodium, potassium, magnesium, calcium salts and the like, saltswith organic bases, e.g. the benzathine, N-methyl-D-glucamine,hydrabamine salts, and salts with amino acids such as, for example,arginine, lysine and the like.

Conversely said salt forms can be converted by treatment with anappropriate base or acid into the free acid or base form.

The term addition salt as used hereinabove also comprises the solvateswhich the compounds of formula (I) are able to form and said solvatesare meant to be included within the scope of the present invention.Examples of such solvates are, e.g. the hydrates, alcoholates and thelike.

The term stereochemically isomeric forms as used herein defines all thepossible isomeric forms in which the compounds of formula (I) may occur.Unless otherwise mentioned or indicated, the chemical designation ofcompounds denotes the mixture of all possible stereochemically isomericforms, said mixtures containing all diastereomers and enantiomers of thebasic molecular structure.

Some of the compounds of formula (I) may also exist in their tautomericforms. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.

Whenever used hereinafter, the term compounds of formula (I) is meant toinclude also the pharmaceutically acceptable addition salts and allstereoisomeric forms.

Interesting compounds are those compounds of formula (I) wherein D is aradical of formula ##STR5## wherein R⁵ is hydrogen or C₁₋₆ alkyl andpreferably is methyl; R⁹ and R¹⁰ each independently are hydrogen or C₁₋₆alkyl; R¹¹ is C₁₋₆ alkyl, hydroxy, C₁₋₆ alkyloxy or C₁₋₁₀alkylcarbonyloxy, and preferably is hydroxy, C₁₋₆ alkyloxy or C₁₋₁₀alkyl-carbonyloxy; and R¹² is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkyloxy, C₁₋₆alkylthio, amino or mono- or di(C₁₋₆ alkyl)amino.

Further interesting compounds are those compounds of formula (I) whereinR³ and R⁴ are both hydrogen.

In a first subset of compounds of formula (1), Alk is C₂₋₄ alkanediyl.

In a second subset of compounds of formula (I), R¹ is hydrogen orhalogen and R² is hydrogen.

In a third subset of compounds of formula (I), the substituent on the 4position of the piperidinyl is an 1H-indole, i.e. the dashed linerepresents an extra bond.

In a fourth subset of compounds of formula (I), the substituent on the 4position of the piperidinyl is an 2,3-dihydro-1H-indole.

Preferred compounds are those compounds of formula (I) wherein R¹ ishydrogen or fluor; R², R³ and R⁴ are hydrogen; Alk is 1,2-ethanediyl; Dis a radical of formula (a) wherein R⁵ is methyl; R⁶ is C₁₋₆ alkylaminoand R⁷ is C₁₋₆ alkyl; or R⁶ and R⁷ taken together may form a bivalentradical of formula (a-2) or (a-5) wherein one hydrogen atom of saidradicals (a-2) and (a-5) may be replaced by C₁₋₆ alkyl, hydroxy or C₁₋₆alkyloxy; or R⁶ and R⁷ taken together may form a bivalent radical offormula (a-6), (a-7), (a-8), (a-13) or (a-14) wherein one or wherepossible two hydrogen atoms may be replaced by C₁₋₆ alkyl.

More preferred compounds are those preferred compounds wherein thesubstituent on the 4 position of the piperidinyl is an indole wherein R¹is substituted in the 5 position and stands for hydrogen or fluor.

Most preferred compounds are selected from

3- 2-4-(5-fluoro-1H-indol-1-yl)-1-piperidinyl!ethyl!-6,7,8,9-tetrahydro-2-methyl-4H-pyrido1,2-a!pyrimidin-4-one;

6- 2-4-(5-fluoro-1H-indol-1-yl)-1-piperidinyl!ethyl!-7-methyl-5H-thiazolo3,2-a!-pyrimidin-5-one;

5- 2-4-(5-fluoro-1H-indol-1-yl)-1-piperidinyl!ethyl!-3,6-dimethyl-2-(methylamino)-4(3H)-pyrimidinone;and

2,3-dihydro-6 2-4-(1H-indol-1-yl)-1-piperidinyl!ethyl!-7-methyl-5H-thiazolo3,2-a!-pyrimidin-5-one;

the pharmaceutically acceptable addition salts and the stereochemicallyisomeric forms thereof.

The compounds of formula (I) can generally be prepared by N-alkylating a1-(piperidin-4-yl)-1H-indole derivative of formula (II) with analkylating reagent of formula (III) following the procedure described inEP-A-0,037,265, EP-A-0,070,053, EP-A-0,196,132 and in EP-A-0,378,255.##STR6##

In the following intermediates, the dashed line and the radicals D, Alkand R¹ to R⁴ are defined as under formula (1) unless otherwisespecified. In intermediate (III), W represents an appropriate reactiveleaving group such as, for example, halo, e.g. chloro, bromo or iodo;sulfonyloxy, e.g. methanesulfonyloxy, 4-methylbenzenesulfonyloxy.

In this and the following preparations, the reaction products may beisolated from the reaction medium and, if necessary, further purifiedaccording to methodologies generally known in the art such as, forexample, extraction, crystallization, trituration and chromatography.

Compounds of formula (1) wherein R³ and R⁴ are hydrogen and theheterocyclic moiety in the 4 position of the piperidine ring is an1H-indole, said compounds being represented by formula (I-f), mayalternatively be prepared by cyclizing an intermediate of formula (IV)wherein W is a reactive leaving group such as, for example, halo, e.g.chloro, bromo or iodo; sulfonyloxy, e.g. methanesulfonyloxy,4-methylbenzene-sulfonyloxy, in the presence of a reductant such as, forexample, a complex metal hydride, e.g. sodium borohydride. Saidprocedure is described in Synthetic Communications, 18(3), 265-273(1988). ##STR7##

EP-A-0,037,265, EP-A-0,070,053, EP-A-0,196,132 and EP-A-0,378,255describe other alternative procedures to prepare compounds of formula(I). Furthermore, the compounds of formula (I) may be converted intoeach other following art-known functional group transformationreactions.

A number of intermediates and starting materials are known compoundswhich may be prepared according to art-known methodologies. For example,intermediates of formula (III) and their preparations are described inEP-A-0,037,265, EP-A-0,070,053, EP-A-0,196,132 and in EP-A-0,378,255.

Intermediates of formula (II) can be prepared following art-knownprocedures, e.g. by reductively aminating a ketone of formula (V),wherein P is a protecting group such as, for example, analkyloxycarbonyl group, with an indole derivative of formula (VI), andsubsequently removing the protecting group P by art-known deprotectiontechniques. ##STR8##

Said reductive amination may conveniently be carried out by mixing thereactants in a suitable reaction-inert solvent such as, for example,methanol or toluene, with an appropriate reductant. Preferably, theketone of formula (V) is first reacted with the indole derivative offormula (VI) to form an enamine, which is subsequently reduced. Hydrogenin the presence of a suitable catalyst such as, for example, palladiumor platinum supported on for instance charcoal may be used as anappropriate reductant. Elevated pressure and/or temperature may enhancethe rate of the reaction. In order to prevent the undesired furtherhydrogenation of certain functional groups in the reactants and thereaction products, it may be advantageous to add an appropriate catalystpoison to the reaction mixture such as, for example, thiophene.

The intermediates of formula (VI) wherein the dashed line represents anextra bond and R³ and R⁴ are both hydrogen, may be prepared as describedin Journal of Heterocyclic Chemistry, 2, 298-299 (1965).

Some of the compounds of formula (I) and some of the intermediates inthe present invention contain at least one asymmetric carbon atom. Purestereochemically isomeric forms of said compounds and said intermediatescan be obtained by the application of art-known procedures. For example,diastereoisomers can be separated by physical methods such as selectivecrystallization or chromatographic techniques, e.g. counter currentdistribution, liquid chromatography and the like methods. Enantiomerscan be obtained from racemic mixtures by first converting said racemicmixtures with suitable resolving agents such as, for example, chiralacids, to mixtures of diastereomeric salts or compounds; then physicallyseparating said mixtures of diastereomeric salts or compounds by, forexample, selective crystallization or chromatographic techniques, e.g.liquid chromatography and the like methods; and finally converting saidseparated diastereomeric salts or compounds into the correspondingenantiomers.

Pure stereochemically isomeric forms of the compounds of formula (I) mayalso be obtained from the pure stereochemically isomeric forms of theappropriate intermediates and starting materials, provided that theintervening reactions occur stereospecifically. The pure and mixedstereochemically isomeric forms of the compounds of formula (I) areintended to be embraced within the scope of the present invention.

The compounds of formula (I), the pharmaceutically acceptable additionsalts and stereochemically isomeric forms thereof, are antagonists ofneurotransmitters and in particular of the mediators serotonin anddopamine. Antagonizing said mediators will suppress or relieve a varietyof symptoms associated with phenomena induced by the release, inparticular the excessive release, of these mediators. Therapeuticindications for using the present compounds are mainly in the CNS area,especially in psychotic disorders. Further, serotonin is a potentbroncho- and vasoconstrictor and thus the present antagonists may beused against hypertension and vascular disorders. In addition, serotoninantagonists have been associated with a number of other properties suchas, the suppression of appetite and promotion of weight loss, which mayprove effective in combatting obesity; and also the alleviation ofwithdrawal symptoms in addicts trying to discontinue drinking andsmoking habits. The present compounds also appear to be usefultherapeutic agents for combatting autism.

In view of the usefulness of the subject compounds in the treatment ofdiseases associated with the release of neurotransmitters, in particularin the treatment of psychotic diseases, the present invention provides amethod of treating warm-blooded animals suffering from such diseases, inparticular psychotic diseases, said method comprising the systemicadministration of an antipsychotic amount of a compound of formula (I)or a pharmaceutically acceptable addition salt thereof, effective intreating diseases associated with the release of neurotransmitters, inparticular psychotic diseases. Those of skill in the treatment of suchdiseases could readily determine the effective amount from the testresults presented hereinafter. In general it is contemplated that aneffective antipsychotic daily amount would be from about 0.01 mg/kg toabout 4 mg/kg body weight, more preferably from about 0.04 mg/kg toabout 2 mg/kg body weight.

The present invention thus also relates to compounds of formula (I) asdefined hereinabove for use as a medicine. Further, the presentinvention also relates to the use of a compound of formula (I) for themanufacture of a medicament for treating psychotic diseases.

The "apomorphine, tryptamine, norepinephrine (ATN) test in rats" is usedto evaluate dopamine antagonism, serotonin antagonism and α-adrenergicantagonistic properties of the compounds of formula (I). In said test,which is described hereinafter, rats are observed for effects which areindicative for peripheral and central activity of the tested compounds.Centrally acting serotonin antagonists are potential antipsychoticdrugs, in particular when simultaneously displaying dopamine antagonism.Peripheral serotonin antagonists are potentially useful in thegastro-intestinal and cardiovascular field, in particular whensimultaneously displaying α-adrenergic antagonistic activity. Thecompounds of the present invention show a strong central dopamine andserotonin antagonism and little peripheral α-adrenergic antagonisticactivity. In view of the central dopamine and serotonin antagonisticactivity of the compounds of formula (I), they are particularly usefulin combatting psychoses, aggressive behaviour, anxiety, depression andmigraine. Furthermore, the improved dissociation between peripheralα-adrenergic antagonistic activity and central dopamine and serotoninantagonistic activity of the compounds of formula (I) over prior knownantipsychotic agents, leads to an increased cardiovascular safety, i.e.a decreased likelihood of hypotension.

For administration purposes, the subject compounds may be formulatedinto various pharmaceutical forms. To prepare the pharmaceuticalcompositions of this invention, an effective amount of the particularcompound, in addition salt or in free acid or base form, as the activeingredient is combined in intimate admixture with a pharmaceuticallyacceptable carrier, which may take a wide variety of forms depending onthe form of preparation desired for administration. These pharmaceuticalcompositions are desirably in unitary dosage form suitable, preferably,for administration orally, percutaneously, or by parenteral injection.For example, in preparing the compositions in oral dosage form, any ofthe usual pharmaceutical media may be employed, such as, for example,water, glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs and solutions; orsolid carriers such as starches, sugars, kaolin, lubricants, binders,disintegrating agents and the like in the case of powders, pills,capsules and tablets. Because of their ease in administration, tabletsand capsules represent the most advantageous oral dosage unit form, inwhich case solid pharmaceutical carriers are obviously employed. Forparenteral compositions, the carrier will usually comprise sterilewater, at least in large part, though other ingredients, for example, toaid solubility, may be included. Injectable solutions, for example, maybe prepared in which the carrier comprises saline solution, glucosesolution or a mixture of saline and glucose solution. Injectablesolutions containing compounds of formula (I) may be formulated in anoil for prolonged action. Appropriate oils for this purpose are, forexample, peanut oil, sesame oil, cottonseed oil, corn oil, soy bean oil,synthetic glycerol esters of long chain fatty acids and mixtures ofthese and other oils. Injectable suspensions may also be prepared inwhich case appropriate liquid carriers, suspending agents and the likemay be employed. In the compositions suitable for percutaneousadministration, the carrier optionally comprises a penetration enhancingagent and/or a suitable wettable agent, optionally combined withsuitable additives of any nature in minor proportions, which additivesdo not cause any significant deleterious effects on the skin. Saidadditives may facilitate the administration to the skin and/or may behelpful for preparing the desired compositions. These compositions maybe administered in various ways, e.g., as a transdermal patch, as aspot-on or as an ointment. Addition salts of (I) due to their increasedwater solubility over the corresponding free base or free acid form, areobviously more suitable in the preparation of aqueous compositions.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect, in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

The following examples are intended to illustrate and not to limit thescope of the present invention.

EXPERIMENTAL PART

Hereinafter, "RT" means room temperature and "DIPE" means diisopropylether.

A. Preparation of the intermediates

EXAMPLE 1

a) Sodium methylate (1260.5 g) was added dropwise to a suspension ofthiourea (373 g) in ethanol (1750 ml) and the dropping funnel was rinsedwith ethanol (175 ml). The mixture was heated to 40° C. and3-acetyldihydro-2(3H)-furanone (448.5 g) was added dropwise. Thedropping funnel was rinsed with ethanol (475 ml) and the reactionmixture was stirred and refluxed for 6.25 hours. Stirring was continuedfor 2 hours, while cooling. The solvent was evaporated and the residuewas dissolved in water (2800 ml). This mixture was cooled on ice andneutralized with hydrochloric acid (490 ml) The precipitate was filteredoff, washed with water (350 ml) and dried, yielding 268 g (41.1%) of5-(2-hydroxyethyl)-2-mercapto-6-methyl-4(3H)-pyrimidinone (intermediate1).

b) A mixture of intermediate 1 (37.2 g) and sodium methylate (36 g) inmethanol (250 ml) was stirred for 30 min. Ethane iodide (31.2 g) wasadded dropwise. The reaction mixture was stirred and refluxed for 3hours. The solvent was evaporated and the residue was stirred in water,filtered and recrystallized from CH₃ CN. The precipitate was filteredoff and dried, yielding 26 g (60%) of2-(ethylthio)-5-(2-hydroxyethyl)-6-methyl-4(3H)-pyrimidinone(intermediate 2).

c) Potassium hydroxide (8.4 g) was added to a solution of intermediate 2(33 g) in dimethyl sulfoxide (150 ml). The mixture was stirred for 1hour at 60-70 ° C. The mixture was cooled to 20° C. and iodomethane(21.3 g) was added dropwise. The reaction mixture was stirred overnightat RT. The mixture was poured out into water and extracted with toluene.The separated organic layer was dried, filtered and the solvent wasevaporated. The residue was crystallized from 4-methyl-2-pentanone andthe precipitate was filtered off and dried, yielding 16 g (46%) of2-(ethylthio)-5-(2-hydroxy-ethyl)-3,6-dimethyl-4(3H)-pyrimidinone(intermediate 3).

EXAMPLE 2

a) 3-acetyldihydro-2(3H)-furanone (25.6 g) was added to a stirredmixture of acetamidine hydrochloride (20 g) and sodium methylate (110 g)in methanol (150 ml). The reaction mixture was stirred and refluxedovernight. The reaction mixture was cooled and acetic acid (36 g) wasadded dropwise. The precipitate was filtered off and the filtrateevaporated. The residue was purified by column chromatography oversilica gel (eluent: CHCl₃ /(CH₃ OH/NH₃) 90/10). The pure fractions werecollected and the solvent was evaporated. The residue was crystallizedfrom 2-propanol. The crystals were filtered off and dried, yielding 7.6g (22%) of 5-(2-hydroxyethyl)-2,6-dimethyl-4(3H)-pyrimidinone(intermediate 4).

b) Sodium methylate (1.9 g) was added to a mixture of intermediate 4 (6g) in methanol (50 ml) while stirring at RT. Stirring was continued for30 minutes and iodomethane (5 g) was added dropwise and the reactionmixture was stirred and refluxed for 4 hours. The solvent wasevaporated, water was added to the residue and this mixture wasextracted with CH₂ Cl₂. The organic layer was separated, dried overMgSO₄, filtered and the solvent was evaporated, yielding 6.0 g (94%) of5-(2-hydroxyethyl)-2,3,6-trimethyl-4(3H)-pyrimidinone (intermediate 5).

EXAMPLE 3

a) A mixture of ethyl 4-oxo-1-piperidinecarboxylate (85 g) and2,3-dihydro-1H-indole (60 g), palladium on activated carbon (10%) (4 g)and a solution of thiophene in isopropyl ether (4%) (2 ml) in methanol(700 ml) was reacted in a Parr Pressure Vessel at 50° C. overnight.After completion, the mixture was filtered and the filtrate wasevaporated, yielding 80 g (58%) of ethyl4-(2,3-dihydro-1Hindol-1-yl)-1-piperidine-carboxylate (intermediate 6)

b) A mixture of intermediate 6 (95 g) and potassium hydroxide (194 g) in2-propanol (1300 ml) was stirred and refluxed for 24 hours. The solventwas evaporated and the residue was dissolved in H₂ O/CH₂ Cl₂. Theorganic layer was separated, dried over MgSO₄, filtered and evaporated,yielding 64 g (90.4%) of 2,3-dihydro-1-(4-piperidinyl)-1H-indole. Asample (4.5 g) was crystallized from CH₃ OH and converted into thehydrochloric acid salt (1:1) in 2-propanol and filtered off, yielding3.0 g of 2,3-dihydro-1-(4-piperidinyl)-1H-indole monohydrochloride(intermediate 7).

EXAMPLE 4

A mixture of 2-bromoethanol (3.75 g), 1-(4-piperidinyl)-1H-indole (5 g)and sodium hydrogen carbonate (4.2 g) in ethanol (100 ml) was stirredand refluxed overnight. The solvent was evaporated. The residue wasstirred in water and this mixture was extracted with CH₂ Cl₂. Theseparated organic layer was dried over MgSO₄, filtered and the solventwas evaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂ Cl₂ /CH₃ OH 95/5). The pure fractions werecollected and the solvent was evaporated. The residue was stirred inDIPE and the solvent was evaporated, yielding 4 g (64%) of4-(1H-indol-1-yl)-1-piperidineethanol (intermediate 8).

EXAMPLE 5

a) A mixture of 2-amino-3-pyridinol (100 g),3-acetyldihydro-2(3H)-furanone (100 g), 4-methylbenzene sulfonic acid (1g) and xylene (700 ml) was stirred and refluxed overnight using a waterseparator. The mixture was cooled and the product was filtered off anddried. The product was converted into the hydrochloric acid salt in2-propanol. The salt was filtered off and dried, yielding 120 g (58.4%)of 9-hydroxy-3-(2-hydroxy-ethyl)-2-methyl-4H-pyrido1,2-a!pyrimidin-4-one monohydrochloride (intermediate 9).

b) Dimethyl sulfate (2.52 g) was added dropwise to a mixture ofintermediate 9 (4.4 g) and sodium hydroxide (0.8 g) in water (10 ml),while cooling in ice water. The reaction mixture was stirred for 15minutes at RT, then it was heated for 1 hour using a warm water bath.The reaction mixture was cooled and extracted with CH₂ Cl₂. Theprecipitate in the separated aqueous layer was filtered off and purifiedby column chromatography over silica gel (eluent: CH₂ Cl₂ /CH₃ OH 97/3).The pure fractions were collected and the solvent was evaporated. Theresidue was crystallized from CH₃ CN. The crystals were filtered off anddried, yielding 2 g (42%) of3-(2-hydroxyethyl)-9-methoxy-2-methyl-4H-pyrido 1,2-a!pyrimidin-4-one(intermediate 10).

c) A mixture of intermediate 10 (14 g) in methanol (250 ml) washydrogenated at 50° C. with palladium on activated carbon (10%) (2 g) asa catalyst. After uptake of hydrogen (2 eq.), the catalyst was filteredoff. The filtrate was evaporated and the residue was purified by columnchromatography over silica gel (eluent: CH₂ Cl₂ /CH₃ OH 95/5). The purefractions were collected and the solvent was evaporated, yielding 10 g(71%) of(±)-6,7,8,9-tetrahydro-3-(2-hydroxyethyl)-9-methoxy-2-methyl-4H-pyrido1,2-a!-pyrimidin-4-one(intermediate 11).

EXAMPLE 6

Methanesulfonyl chloride (3.43 g) was added dropwise to a stirred andcooled (ice water bath) mixture of intermediate 13 (7 g) andN,N-diethylethanamine (3 g) in dichloro-methane (50 ml). The reactionmixture was stirred for 2 hours at RT. The reaction mixture was washedwith water and the organic layer was separated, dried over MgSO₄,filtered and the solvent was evaporated, yielding 8 g (84%) of(±)-6,7,8,9-tetrahydro-9-methoxy-2-methyl-3- 2-(methylsulfonyl)oxy!ethyl!-4H-pyrido 1,2-a!pyrimidin-4-one (intermediate12).

In a similar way, 2-(ethylthio)-3,6-dimethyl-5-2-(methylsulfonyl)oxy!ethyl!-4(3H)-pyrimidinone hemihydradate(intermediate 13) was prepared from intermediate 3 and2,3,6-trimethyl-5- 2-(methylsulfonyl)oxy!ethyl!-4(3H)-pyrimidinone(intermediate 14) was prepared from intermediate 5.

EXAMPLE 7

a) A mixture of intermediate 9 (170 g) and hydrobromic acid (48%) (1000ml) was stirred and refluxed overnight. The mixture was cooled and theprecipitate was filtered off, yielding a first fraction of 100 g. Thefiltrate was evaporated, yielding a second fraction of 30 g. Bothfractions were recrystallized from water, yielding 75 g (34%) of3-(2-bromoethyl)-9-hydroxy-2-methyl-4H-pyrido 1,2-a!pyrimidin-4-onemonohydro-bromide (intermediate 15).

b) A mixture of intermediate 15 (55 g) and hydrobromic acid (48%) (55 g)in methanol (700 ml) was hydrogenated with palladium on activated carbon(10%) (5 g) as a catalyst. After completion, the precipitate wasfiltered off and the filtrate evaporated. Ammonium hydroxide was addedto the residue which was subsequently extracted with CHCl₃. Theseparated organic layer was dried and evaporated. The residue waspurified by column chromatography over silica gel (eluent: CHCl₃ /CH₃ OH90/10). The pure fractions were collected, the solvent was evaporatedand the residue was recrystallized from 4-methyl-2-pentanone, yielding17 g (44%) of(±)-6,7,8,9-tetrahydro-3-(2-bromoethyl)-9-hydroxy-2-methyl-4H-pyrido1,2-a!pyrimidin-4-one (intermediate 16).

B. Preparation of the compounds of formula (I)

EXAMPLE 8

A mixture of 1-(4-piperidinyl)-1H-indole (4.1 g),6-(2-chloroethyl)-7-methyl-5H-thiazolo 3,2-a!pyrimidin-5-one (3.4 g),prepared as described in EP-A-0,196,132, sodium carbonate (6 g) andpotassium iodide (0.1 g) in 4-methyl-2-pentanone (250 ml) was stirredand refluxed overnight. The warm reaction mixture was filtered and thefiltrate was evaporated. The residue was purified over silica gel on aglass filter (eluent: CH₂ Cl₂ /C₂ H₅ OH 90/10). The pure fractions werecollected and the solvent was evaporated. The residue was crystallizedfrom DIPE with a small amount of CH3CN. The precipitate was filtered offand dried, yielding 3 g (51%) 6- 2-4-(1H-indol-1-yl)-1-piperidinyl!ethyl!-7-methyl-5H-thiazolo3,2-a!pyrimidin-5-one (compound 3; mp. 134.4° C.).

EXAMPLE 9

6- 2- 4-(1H-indol-1-yl)-1-piperidinyl!ethyl!-3,7-dimethyl-5H-thiazolo3,2-a!pyrimidin-5-one was prepared according to the procedure describedin example 7 without the presence of potassium iodide (compound 6; mp.189.8° C.).

EXAMPLE 10

A mixture of 6-(2-chloroethyl)-2,7-dimethyl-5H-1,3,4-thiadiazolo3,2-a!pyrimidin-5-one (3.6 g), prepared as described in EP-A-0,353,821,5-fluoro-1-(4-piperidinyl)-1H-indole (3.3 g), prepared according to theprocedure described in Synthetic Communications, 18 (3), 265-273 (1988),sodium carbonate (1 g), potassium iodide (catalytic quantity) and sodiumhydrogen carbonate (2 g) in 4-methyl-2-pentanone (150 ml) and2-ethoxyethanol (50 ml) was stirred and refluxed overnight. The mixturewas filtered and the filtrate was washed with water. The organic layerwas separated, dried, filtered and the solvent evaporated. The residuewas purified by column chromatography over silica gel (eluent: CH₂ Cl₂/CH₃ OH 95/5). The pure fractions were collected and the solvent wasevaporated. The residue was crystallized from DIPE/CH3CN. Theprecipitate was filtered off, dried and purified by high-performanceliquid chromatography over RP-18 (eluent: (0.5% NH₄ OAc in H₂ O)/CH₃OH/THF 50/40/10). The pure fractions were collected and the solvent wasevaporated, yielding 1.37 g (20%) 6- 2-4-(5-fluoro-1H-indol-1-yl)-1-piperidinyl!-ethyl!-2,7-dimethyl-5H-1,3,4-thiadiazolo3,2-a!pyrimidin-5-one (compound 8; mp. 194.1° C.).

EXAMPLE 11

A mixture of 6-(2-bromoethyl)-1,2,7-trimethyl-1H,5H-imidazo1,2-a!pyrimidin-5-one (8.85 g), prepared as described in EP-0,378,255,1-(4-piperidinyl)-1H-indole (2 g) and N-(1-methylethyl)-2-propanamine(1.2 g) in ethanol (100 ml) was stirred and refluxed for 6 hours. Thesolvent was evaporated and the residue was stirred in water andsubsequently extracted with CH₂ Cl₂. The separated organic layer wasdried, filtered and the solvent was evaporated. The residue was purifiedby column chromatography over silica gel (eluent: CH₂ Cl₂ /CH₃ OH 95/5).The pure fractions were collected and the solvent was evaporated. Theresidue was crystallized from CH₃ CN/DIPE and the precipitate wasfiltered off and dried, yielding 2.5 g (62%) 6- 2-4-(1H-indol-1-yl)-1-piperidinyl!ethyl!-1,2,7-trimethylimidazo1,2-a!pyrimidin-5(1H)-one (compound 9; mp. 165.7° C.).

EXAMPLE 12

1-(2-bromoethyl)-2H-benzimidazol-2-one (4.8 g) was added to a mixture of1-(4-piperidinyl)-1H-indole (5.6 g), sodium methylate (1 g) and sodiumcarbonate (5 g) in 4-methyl-2-pentanone (250 ml). The reaction mixturewas stirred and refluxed overnight. The mixture was filtered while stillwarm. The filtrate was evaporated. The residue was purified over silicagel on a glass filter (eluent: CH₂ Cl₂ /C₂ H₅ OH 90/10). The purefractions were collected and the solvent was evaporated. The residue wasdissolved in warm ethanol and converted into the (E)-2-butenedioic acidsalt (1:1). The mixture was cooled. The precipitate was filtered off anddried, yielding: 8.7 g (91%) 1,3-dihydro-1- 2-4-(1H-indol-1-yl)-1-piperidinyl!ethyl!-2H-benzimidazol-2-one(E)-2-butenedioate (1:1) (compound 26; mp. 205.3° C.)

EXAMPLE 13

A mixture of 5-fluoro-1-(4-piperidinyl)-1H-indole (3.2 g),1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one (3 g),N,N-diethylethanamine (3 ml) and potassium iodide (0.1 g) in toluene(200 ml) was stirred and refluxed overnight. The reaction mixture wascooled, washed with water and the organic layer was separated, dried,filtered and the solvent was evaporated. The residue was purified bycolumn chromatography over silica gel (eluent: CH₂ Cl₂ /CH₃ OH 95/5).The pure fractions were collected and the solvent was evaporated. Theresidue was dissolved in ethanol and converted into the(E)-2-butenedioic acid salt (1:1). The mixture was allowed to cool,while stirring. The precipitate was filtered off and dried, yielding 3 g(42%) 1- 3-4-(5-fluoro-1H-indol-1-yl)-1-piperidinyl!propyl!-1,3-dihydro-2H-benzimidazol-2-one(E)-2-butenedioate (1:1) (compound 28; mp. 192.5° C.).

Tables 1 to 4 list similar compounds that were prepared according to oneof the above described examples.

                                      TABLE 1    __________________________________________________________________________    Co.       Ex.                           Phys. Data    No.       No.          R.sup.1               R.sup.3                   R.sup.4                       --R.sup.6 --R.sup.7--                                     (mp in ° C.)    __________________________________________________________________________     1  9 H    H   H   --S--CH.sub.2 --CH.sub.2 --                                     190.2     2  9 F    H   H   --S--CH.sub.2 --CH.sub.2 --                                     200.0     3  8 H    H   H   --S--CH═ CH--                                     134.4     4  8 F    H   H   --S--CH═ CH--                                     126.6     6  9 H    H   H   --S--CH═ C(CH.sub.3)--                                     189.8     8 10 F    H   H   --S--C(CH.sub.3)═ N--                                     194.1     9 11 H    H   H   --N(CH.sub.3)--C(CH.sub.3)═ CH--                                     165.7    10  8 F    H   H   --CH═ C(CH.sub.3)--O--                                     208.4    11  8 H    H   H   --(CH.sub.2).sub.4 --                                     142.3    12  8 F    H   H   --(CH.sub.2).sub.4 --                                     173.8    13 11 H    H   H   --CH(OH)--(CH.sub.2).sub.3 --                                     (±)/154.4    14 11 F    H   H   --CH(OH)--(CH.sub.2).sub.3 --                                     (±)/192.0    15 11 F    H   H   --CH(OCH.sub.3)--(CH.sub.2).sub.3 --                                     (±)/159.6    16  9 H    H   H   --S--(CH.sub.2).sub.3 --                                     153.0    17  9 F    H   H   --S--(CH.sub.2).sub.3 --                                     173.1    18 13 F    H   H   --CH═ CH--CH═ CH--                                     144.4    19  8 H    H   H   --C(CH.sub.3)═ CH--CH═ CH--                                     127.6    20  8 F    H   H   --C(CH.sub.3)═ CH--CH═ CH--                                     165.9    29 11 F    H   H   --(CH.sub.2).sub.3 --CH(CH.sub.3)--                                     165.9    30 11 F    --CH.sub.3                   --C.sub.6 H.sub.5                       --(CH.sub.2).sub.4 --                                     147.7    32 11 H    --CH.sub.3                   H   --(CH.sub.2).sub.4 --                                     140.2    33 11 --OCH.sub.3               H   H   --(CH.sub.2).sub.4 --                                     154.7    36 11 H    --CH.sub.3                   --CH.sub.3                       --(CH.sub.2).sub.4 --                                     149.2    37 11 --CH.sub.3               H   H   --(CH.sub.2).sub.4 --                                     161.2    38 11 Cl   H   H   --(CH.sub.2).sub.4 --                                     184.0    __________________________________________________________________________

                  TABLE 2    ______________________________________    Co.  Ex.                                 Phys. Data    No.  No.    R.sup.1                      R.sup.3                            R.sup.4                                  --R.sup.6 --R.sup.7--                                             (mp in ° C.)    ______________________________________     5   11     H     H     H     --S--CH═CH--                                             143.4    31   11     H     H     H     --(CH.sub.2).sub.4 --                                             119.2    34   11     H     --CH.sub.3                            H     --(CH.sub.2).sub.4 --                                             99.4    35   11     H     --CH.sub.3                            --CH.sub.3                                  --(CH.sub.2).sub.4 --                                             123.7    ______________________________________

                  TABLE 3    ______________________________________                                    Physic. Data (mp. in    Co. No.          Ex. No.  R.sup.1                         R.sup.6    ° C.)    ______________________________________    21    11       H     --CH.sub.3 119.5    22    11       H     --NH.sub.2 210.7    23     8       H     --NH--CH.sub.3                                    171.9    24     8       F     --NH--CH.sub.3                                    179.8    25    11       H     --S--CH.sub.2 --CH.sub.3                                    129.5    ______________________________________

                  TABLE 4    ______________________________________    Co. No.           Ex. No.  R.sup.1                           n    x    Phys. Data (mp. in ° C.)    ______________________________________    26     12       H      2    1    205.3    27      9       F      2    1/2  179.8    28     13       F      3    1    192.5    ______________________________________     C. Pharmacological Example

EXAMPLE 14 "apomorphine, tryptamine, norepinephrine (ATN) test in rats"

The antipsychotic activity of the subject compounds is evidenced by theexperimental data obtained in the combined apomorphine (APO), tryptamine(TRY) and norepinephrine (NOR) test in rats. Said combined apomorphine,tryptamine and norepinephrine test is described in Arch. Int.Pharmacodyn., 227, 238-253 (1977) and provides an empirical evaluationof the relative specificity with which drugs may effect particularneurotransmitter systems centrally (CNS) as well as peripherally. Inparticular, the test demonstrates the antagonistic activity of thetested compounds of formula (I) on dopamine (by preventing the symptomselicited with the dopamine agonist apomorphine), on serotonin (bypreventing the central symptoms (convulsions) and peripheral symptoms(hyperaemia) elicited with serotonin or tryptamine), and onnorepinephrine (by preventing or delaying death upon administration ofthe α-agonist norepinephrine). The favourable pharmacological propertyof the compounds of formula (I) lies in the absence of a strongα-adrenergic antagonistic activity (column NOR) laeding to an improveddissociation between peripheral α-adrenergic antagonistic activity andcentral serotonin (column TRY convulsions) and central dopamine (columnAPO) antagonistic activity.

The test is carried out following the procedures described inEP-A-0,196,132 and the experimental data are summarized in Table 5.

                  TABLE 5    ______________________________________             Combined test in rats, ED.sub.50 in mg/kg    Compound          TRY         TRY    Number     APO    convulsions hyperaemia                                          NOR    ______________________________________    1          0.63   0.63        0.04    >10    2          0.16   0.63        0.01     10    3          0.16   0.16        0.01    >10    4          0.04   0.04        0.01      2.5    5          0.08   0.31        0.02    >10    6          0.16   0.16        0.01     10    7          0.63   2.5         0.04    >10    8          0.63   0.63        0.04     10    10         0.63   0.16         0.0025  10    12         0.31   0.31        0.02    >10    15         0.16   0.63        0.01     10    16         0.16   0.63        0.02     10    17         0.08   0.16        0.02     5    18         0.08   0.08        0.01     5    19         0.63   2.5         0.63    >10    20         0.63   0.63        0.16    >10    24         0.63   0.16        0.01     10    25         0.63   2.5         0.16    >10    28         0.16   0.16        0.01    >10    29         0.08   0.31         0.005   5    31         1.25   1.25        0.31    >10    34         5      >10         ≦0.63                                          ≧10    ______________________________________

D. Composition examples

"Active ingredient" (A.I.) as used throughout these examples relates toa compound of formula (I), a pharmaceutically acceptable addition saltor a stereochemically isomeric form thereof.

EXAMPLE 15 Capsules

20 g of the A.I., 6 g sodium lauryl sulfate, 56 g starch, 56 g lactose,0.8 g colloidal silicon dioxide, and 1.2 g magnesium stearate arevigorously stirred together. The resulting mixture is subsequentlyfilled into 1000 suitable hardened gelatin capsules, each comprising 20mg of the A.I.

EXAMPLE 16 Film-coated tablets

Preparation of tablet core

A mixture of 100 g of the A.I., 570 g lactose and 200 g starch is mixedwell and thereafter humidified with a solution of 5 g sodium dodecylsulfate and 10 g polyvinyl-pyrrolidone in about 200 ml of water. The wetpowder mixture is sieved, dried and sieved again. Then there are added100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil.The whole is mixed well and compressed into tablets, giving 10.000tablets, each comprising 10 mg of the active ingredient.

Coating

To a solution of 10 g methyl cellulose in 75 ml of denaturated ethanolthere is added a solution of 5 g of ethyl cellulose in 150 ml ofdichloromethane. Then there are added 75 ml of dichloromethane and 2.5ml 1,2,3-propanetriol. 10 g of polyethylene glycol is molten anddissolved in 75 ml of dichloromethane. The latter solution is added tothe former and then there are added 2.5 g of magnesium octadecanoate, 5g of polyvinylpyrrolidone and 30 ml of concentrated colour suspensionand the whole is homogenated. The tablet cores are coated with the thusobtained mixture in a coating apparatus.

EXAMPLE 17 Oral solution

9 Grams of methyl 4-hydroxybenzoate and 1 gram of propyl4-hydroxybenzoate were dissolved in 41 of boiling purified water. In 3 lof this solution were dissolved first 10 grams of2,3-dihydroxybutanedioic acid and thereafter 20 grams of the A.I. Thelatter solution was combined with the remaining part of the formersolution and 12 l 1,2,3-propanetriol and 3 l of sorbitol 70% solutionwere added thereto. 40 Grams of sodium saccharin were dissolved in 0.5 lof water and 2 ml of raspberry and 2 ml of gooseberry essence wereadded. The latter solution was combined with the former, water was addedq.s. to a volume of 20 l providing an oral solution comprising 5 mg ofthe active ingredient per teaspoonful (5 ml). The resulting solution wasfilled in suitable containers.

EXAMPLE 18 Injectable solution

1.8 Grams methyl 4-hydroxybenzoate and 0.2 grams propyl4-hydroxybenzoate were dissolved in about 0.5 l of boiling water forinjection. After cooling to about 50° C. there were added while stirring4 grams lactic acid, 0.05 grams propylene glycol and 4 grams of the A.I.The solution was cooled to room temperature and supplemented with waterfor injection q.s. ad 1 l, giving a solution comprising 4 mg/ml of A.I.The solution was sterilized by filtration and filled in sterilecontainers.

We claim:
 1. A compound of formula ##STR13## a pharmaceuticallyacceptable addition salt or a stereochemically isomeric form thereof,wherein:the dashed line designates an optional bond; R¹ and R² are eachindependently hydrogen, halogen, C₁₋₆ alkyl or C₁₋₆ alkyloxy; R³ and R⁴are each independently hydrogen, C₁₋₆ alkyl, phenyl or phenylsubstituted with one, two or three substituents selected from halo,hydroxy, nitro, cyano, trifluoromethyl, C₁₋₆ alkyl, C₁₋₆ alkyloxy, C₁₋₆alkylthio, mercapto, amino, mono- and di(C₁₋₆ alkyl)amino, carboxyl,C₁₋₆ alkyloxycarbonyl and C₁₋₆ alkylcarbonyl; Alk is C₁₋₄ alkanediyl; Dis a radical of formula ##STR14## wherein R⁵ is hydrogen or C₁₋₆alkyl;R⁶ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkyloxy, C₁₋₆ alkylthio, aminoor mono- or di(C₁₋₆ alkyl)amino; and R⁷ is hydrogen or C₁₋₆ alkyl; or R⁶and R⁷ taken together may form a bivalent radical --R⁶ --R⁷ --, inparticular, --R⁶ --R⁷ -- may be ##STR15## wherein one or two hydrogenatoms of said radicals (a-1) to (a-5) each independently may be replacedby C₁₋₆ alkyl, hydroxy, C₁₋₆ alkyloxy or C₁₋₆ alkylcarbonyloxy; or--R⁶--R⁷ -- may also be ##STR16## wherein one or where possible two or threehydrogen atoms in said radicals (a-6) to (a-14) each independently maybe replaced by C₁₋₆ alkyl;or D is a radical of formula ##STR17## whereinR⁸ is hydrogen or C₁₋₆ alkyl.
 2. A compound according to claim 1,wherein D is a radical of formula ##STR18## wherein R⁵ is defined as inclaim 1; R⁹ and R¹⁰ each independently are hydrogen or C₁₋₆ alkyl; R¹¹is C₁₋₆ alkyl, hydroxy, C₁₋₆ alkyloxy or C₁₋₁₀ alkylcarbonyloxy; and R¹²is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkyloxy, C₁₋₆ alkylthio, amino or mono-or di(C₁₋₆ alkyl)amino.
 3. A compound according to claim 1, wherein Alkis C₂₋₄ alkanediyl.
 4. A compound according to claim 1, wherein R¹ ishydrogen or halogen and R² is hydrogen.
 5. A compound according to claim1, wherein the compound is selected from3- 2-4-(5-fluoro-1H-indol-1-yl)-1-piperidinyl!ethyl!-6,7,8,9-tetrahydro-2-methyl-4H-pyrido1,2-a!pyrimidin-4-one; 6- 2-4-(5-fluoro-1H-indol-1-yl)-1-piperidinyl!ethyl!-7-methyl-5H-thiazolo-3,2-a!-pyrimidin-5-one; 5- 2-4-(5-fluoro-1H-indol-1-yl)-1-piperidinyl!ethyl!-3,6-dimethyl-2-(methylamino)-4(3H)-pyrimidinone;and 2,3-dihydro-6- 2-4-(1H-indol-1-yl)-1-piperidinyl!ethyl!-7-methyl-5H-thiazolo-3,2-a!pyrimidin-5-one; a pharmaceutically acceptable addition salt or astereochemically isomeric form thereof.
 6. A composition comprising apharmaceutically acceptable carrier and, as active ingredient, atherapeutically effective amount of a compound as claimed in claim
 1. 7.A composition comprising a pharmaceutically acceptable carrier and, asactive ingredient, a therapeutically effective amount of a compound asclaimed in claim
 2. 8. A composition comprising a pharmaceuticallyacceptable carrier and, as active ingredient, a therapeuticallyeffective amount of a compound as claimed in claim
 3. 9. A compositioncomprising a pharmaceutically acceptable carrier and, as activeingredient, a therapeutically effective amount of a compound as claimedin claim
 4. 10. A composition comprising a pharmaceutically acceptablecarrier and, as active ingredient, a therapeutically effective amount ofa compound as claimed in claim
 5. 11. A method of treating psychoticdiseases in patients in need of the same which comprises administeringto said patients a therapeutically effective amount of a compound asclaimed in claim
 1. 12. A method of treating psychotic diseases inpatients in need of the same which comprises administering to saidpatients a therapeutically effective amount of a compound as claimed inclaim
 2. 13. A method of treating psychotic diseases in patients in needof the same which comprises administering to said patients atherapeutically effective amount of a compound as claimed in claim 3.14. A method of treating psychotic diseases in patients in need of thesame which comprises administering to said patients a therapeuticallyeffective amount of a compound as claimed in claim
 4. 15. A method oftreating psychotic diseases in patients in need of the same whichcomprises administering to said patients a therapeutically effectiveamount of a compound as claimed in claim 5.